The objective of this proposal is to increase our understanding of the role of magnesium (Mg) depletion in the etiology of osteoporosis. Dietary Mg intake has been associated with bone mass and/or bone loss in aging and postmenopausal osteoporosis. Mg depletion in the rat results in decreased bone growth, osteopenia and increased skeletal fragility. Decreased bone formation and increased bone resorption has been observed in the Mg depleted rat. We hypothesize that Mg depletion results in the development of osteoporosis. Mechanism(s) for the adverse effect of Mg deficiency on the skeleton is unclear but may involve systemic hormones or local factors regulating bone cell activity. Mg depletion in humans results in hypocalcemia, low serum 1,25(OH)2-vitamin D levels and impaired parathyroid hormone (PTH) secretion as well as renal and skeletal resistance to PTH. Mg depletion in animal models shows similar findings. The Mg deficient rat however, unlike other species, develops hypercalcemia rather than hypocalcemia. Extrapolation of alterations in bone and mineral metabolism in the Mg deficient rat cannot therefore be made to humans. A different model of Mg deficiency-induced osteoporosis is needed. We propose to develop a model of Mg deficiency-induced osteoporosis in the aging female mouse. We will induce dietary Mg deficiency for 3 and 6 weeks and assess changes in serum Mg, calcium and PTH. Bone histomorphometry and bone Mg, calcium and phosphorous content will be evaluated. Cytokines are implicated in the development of osteoporosis and serum levels are known to be high in the Mg deficient rat. We will therefore measure serum levels of I1- 1beta and TNFalpha and perform immunohistochemical staining of bone for I1-1beta, I1-6. And TNFalpha. These studies should substantiate our hypothesis that Mg depletion contributes to osteoporosis and explore possible mechanisms. If substantiated, future experiments will be proposed to further define exact mechanisms. The results may have important implications on the prevention of osteoporosis.